The invention relates to under tissue conditions degradable material.
In surgery, it is known to employ implants manufactured of biodegradable (under tissue conditions absorbable) polymers for connecting tissues together, for separating tissues from each other, for temporarily replacing tissues partially or entirely and for guiding the healing or growth of the tissues. It is known to manufacture of partly crystallized thermoplastic, biodegradable polymers strong implant materials by stretching elongated blanks, such as fibres or bars in a manner that the crystalline structure of the materials is modified and directed (oriented) increasing the strength and the stiffness of the material in the orientation direction. Publication U.S. Pat. No. 4,968,317 presents partly crystalline, biodegradable biomaterials, oriented by the drawing technique which can be used when manufacturing e.g. various equipments for fixation of bone fractures. Publication EP-03211761 presents a method for manufacturing oriented, partially crystalline, biodegradable material by cooling the thermoplastic polymer to a temperature lower than its glass-transition temperature, in which the nucleation of the crystals takes place, and by reheating the material to a temperature which is higher than the glass-transition temperature of the material but lower than its melting temperature, and by stretching the material under these conditions to gain orientation.
Publication WPI ACC No: 89-220470/30 presents a surgical biomaterial consisting of molecularly oriented lactic acid polymers or its copolymer with glycol acid, having a crystal content of 10 to 60% in the material and a compression bending strength of 160 to 250 MPa.
Partially crystalline biodegradable polymer materials can be used for manufacturing e.g. various rods, screws, plates etc. to be employed e.g. when repairing bone fractures or damages in connective tissue. The following publications disclose results of applying these types of materials in surgical use: P. Rokkanen et al.: xe2x80x9cUtilisation des implants biodegradables dans le traitement chirurgical des fractures et au cours des ostxc3xa9otomiesxe2x80x9d, Orthop. Traumato 12, (1992), pp. 107-11; E. K. Partio et al.: xe2x80x9cImmobilisierung und Frxc3xchmobilisierung von Malleolarfrak-turen nach Osteosynthese mit resorbierbaren Schraubenxe2x80x9d, Unfall-chirurgie 18(5), (1992), pp. 304-310; H. Pihlaiamxc3xa4ki et al.: xe2x80x9cAbsorbable pins of self-reinforced poly-l-lactic acid for fixation of fractures and osteotomiesxe2x80x9d, J Bone Joint Surg 74-B(6), (1992), pp. 853-857; T. Yamamuro et al.: xe2x80x9cBioabsorbable osteosynthetic implants of ultra high strength poly-L-lactide. A clinical studyxe2x80x9d, Int. Orthop. 18, (1994), pp. 332-340.
Crystalline configuration as such gives the non-oriented biodegradable materials strength and toughness in a manner that they can be employed e.g. in bone surgery, in selected surgical embodiments, such as in healing of non-loaded bone fractures (cf. e.g. S. Vainionpxc3xa4xc3xa4, P. Rok-kanen and P. Txc3x6rmxc3xa4lxc3xa4: xe2x80x9cSurgical applications of biodegradable polymers in human tissuesxe2x80x9d, Prog. Polym. Sci. 14, (1989), pp. 679-716).
Although the partially crystalline biodegradable materials have good, in case of oriented materials even excellent, strength properties, and the strength retention time in vivo can be controlled to a typical term of 1 to 12 months, the disadvantage is very slow degrading of the crystal phase of the material. Numerous researches have found out that partially crystalline, biodegradable materials first degrade at their amorphous (noncrystalline) parts, since degrading starts and is easiest in the amorphous areas of the material, which are situated between the crystalline areas (cf. e.g. E. W. Fischer, H. J. Sterzel, G. Wegner G.: xe2x80x9cInvestigation of the structure of solution grown crystals of lactide copolymers by means of chemical reactionsxe2x80x9d. Kolloid-Z. Polym. 251, (1973), pp. 980-990). As a result of the said heterogeneous degradation, in the last phase of the polymer absorbing, mainly crystalline, very slowly degradable particles are created. In some tissues, these particles can cause harmful side effects, such as swelling in the tissue and pain (cf. e.g. E. J. Bergsma et al.: xe2x80x9cForeign Body Reactions to Resorbable Poly (L-lactide) Bone Plates and Screws Used for the Fixation of Unstable Zygomatic Fracturesxe2x80x9d, J. Oral Maxillofac. Surg. 51, (1993) pp. 666-670).
However, since the non-crystalline (amorphous) biodegradable polymer material has no slowly degradable crystal structures, degradation of amorphous polymer is under tissue conditions faster than degradation of partially crystalline polymer, and due to the lack of crystalline structure, no such harmful tissue reactions can occur when the amorphous polymers are degrading, as described e.g. in the above mentioned publication E. J. Bergsma et al. However, a drawback with amorphous biodegradable polymers is their poor mechanical strength properties. As for the mechanical properties, the amorphous biodegradable materials are either very ductile (xe2x80x9crubber-likexe2x80x9d), if their glass-transition temperature is under the body temperature, or, on the other hand, they are hard and glass-like it their glass-transition temperature is over the body temperature. In every case, the amorphous polymers have relatively weak strength properties.
Insufficient strength of the amorphous, biodegradable polymer implants is found in clinical research as high frequency of breaking of fracture fixations. E.g. the publication K. E. Rehm, H.-J Helling, L. Claes: xe2x80x9cBericht der Arbeitsgruppe Biodegradable Implantexe2x80x9d, Akt. Traumatol. 24 (1994), pp. 70-74 presents clinical results from 57 patients. In the research, various fractures in the cancellous bone area were fixated with biodegradable rods manufactured of amorphous poly-L/DL-lactide (with L/DL ratio of 70/30). In the post-surgical follow-up of the patients, a dislocation of bone fragment was noticed in tour patients, which signifies fies that this complication was found in 7% of the patients. Further, with two patients (3.5 % of the patients) dislocation of the rod head was found. Thus, the total proportion of complications was high: 10.5%. Dislocation of bone fragment and dislocation of rod head show that the strength of the amorphous lactide copolymer, particularly the shear strength, was not sufficient for providing safe healing. This result differs clearly e.g. from the clinical research of H. Pihlajamxc3xa4ki et al.: xe2x80x9cAbsorbable pins of self-reinforced poly-L-lactic acid for fixation of fractures and osteotomiesxe2x80x9d, J. Bone Joint Surg. (Br) Vol. 74-B, (1992), pp. 853-357, using rods of a corresponding type for the fixation of fractures and osteotomies in cancellous bone area, which rods were manufactured of partly crystalline, oriented (self-reinforced) poly-L-lactide. The research comprised 27 fixation-operated patients, in whom no bone fragment dislocations or rod dislocations were found in the post-operation follow-up (8 to 37 months); i.e. the degree of complications was 0%. Since the shear strength of partially crystalline, oriented polylactide rods is more than double compared to that of amorphous, non-oriented polylactide rods (the shear strength of rods used by Pihla-jamxc3xa4ki et al. was 100 to 180 MPa and the shear strength of rods used by Rehm et al. was measured 46 to 54 MPa, cf. Example 1), it is obvious that the high proportion of complications in the research of Rehm et al. was due to insufficient strength properties of the material used in their study. On the other hand, since no slow-absorbtion, crystalline phase is present in the amorphous polymer, absorbing of the amorphous polymer takes place, after loosing the strength, faster than absorbtion of partly crystalline polymer. For example according to the publication of Rehm et al., rods manufactured of amorphous poly-L/DL-lactide were absorbed almost entirely in two years under tissue conditions, whereas according to Bergsma et al., there was a significant quantity of crystalline poly-L-lactide present at the operation site in the patient even after three years and eight months after the implantation. Also Y. Matsususe et al. (xe2x80x9cIn vitro and in vivo studies on bioabsorbable ultra-high-rigidity poly(L-lactide) rods, J. Biomed. Mater. Res. 26, (1992), pp. 1553-1567) noticed that 18 months after the placing of the implant, a significant amount (xe2x88x9230 %) of partly crystalline poly-L-lactide remained in the laboratory animals.
Since the biodegradable implant becomes useless in the patients system after having lost its strength, it would be advantageous that the implant would absorb as soon as possible after loosing its strength.
Thus, crystalline nature gives the biodegradable material its good initial strength, but it retards the final absorbtion of the polymer after the material has lost its strength, and it may even cause harmful chronic complications in certain embodiments. The amorphous material, in its turn, absorbs last but causes the patient risks when healing (danger of dislocation), because of its poor mechanical properties.
It has been surprisingly discovered in this invention that the drawbacks of known partly crystalline and, on the other hand amorphous biodegradable surgical implants can be efficiently eliminated by using in their manufacturing, instead of known materials, amorphous, biodegradable polymer, copolymer or polymer combination oriented and reinforced (self-reinforced) by means of draw technique. The present invention thus presents molecularly oriented, self-reinforced, amorphous, biodegradable surgical biomaterials, their use in the manufacturing of surgical implants, their parts or compounds, and surgical implants, their parts or compounds manufactured of said biomaterials. Said biomaterials and implants manufactured thereof can be used in surgery for connecting together tissues or parts thereof, for separating tissues or parts thereof, for temporarily replacing tissues and/or for guiding healing or growth of tissues. The self-reinforced materials and implants in accordance with the invention surprisingly combine the advantageous prop eties of known biodegradable, partially crystalline and, on the other hand amorphous materials, and simultaneously eliminate the draw-backs of the materials. Materials of the invention have surprisingly an especially good shear strength, they are tough, they retain their strength for long (typically several months in vivo), when slowly degradable polymer is used as raw material, and after having lost their strength they absorb faster than known strong, partly crystalline, corresponding biodegradable biomaterials. When tested, reinforcing can be seen as an increase of the strength values in the entire macroscopic piece. Additionally, materials of the invention can be sterilized by xcex3-radiation without them loosing too much of their advantageous properties.
To obtain the above mentioned objects, under tissue conditions degradable material according to the invention is mainly characterized by what is said in the characterizing part of the accompanying independent claim 1.
The materials according to the invention have proved out to be surprisingly strong and tough in a manner that they can be used in manufacturing various surgical implants to connect tissues or parts thereof to each other, to separate tissues or parts thereof from each other, to temporarily replace tissues and/or to guide healing or growth of tissues. Implants of this type include e.g. various rods, screws, pins, hooks, intramedullary nails, plates, bolts, suture anchors, foils, wires, tubes, stents, spirals or implants of a corresponding type, presented e.g. in publications U.S. Pat. No. 4,743,257, FI Pat. No. 81010, U.S. Pat. No. 4,968,317, FI Pat. No. 84137, FI Pat. No. 85223, FI Pat. No. 82805, PCT/FI 93100014 and PCT/FI93/00015, U.S. Pat. Nos. 5,084,051, 5,059,211, FI Pat. No. 88111 and EP-634152.
The materials of the invention can be manufactured of thermoplastic, amorphous biodegradable polymers, such as L-lactide copolymers containing a large quantity of D-lactide units (e.g. poly L/DL-lactides having 15 to 85 molecular-% of D-units), amorphous copolymers of lactide and glycol, as well as polymer combinations forming amorphous alloys. It is self-evident that the materials of the invention can be manufactured also from other amorphous, biodegradable polymers, like e.g. of polyorthoesters, (see e.g. U.S. Pat. No. 4,304,767), of pseudopoly (amino acids) (see e.g. S. I. Ertel et al., J. Biomed.Mater. Res., 29 (1995) pp. 1337-1378), etc.
Further, materials in accordance with the invention can include as compound agent powder-like ceramic or corresponding materials. such as bone meal, hydroxyl-apatite powder, calcium-phosphate powder and other absorbable ceramic powders or absorbable ceramic fibres, like bioglass fibres.
According to one advantageous embodiment, the material of the invention also contains at least one organic or inorganic bioactive agent or agents, such as antibiotics, chemotherapeutic agents, agents activating the healing of wounds (e.g. angiogenic growth factors), bone growth factors (bone morphogenic proteins [BMPD] etc. Such bioactive materials are particularly advantageous in clinical use, since, in addition to mechanical effect, they also have biochemical, medical and other effects for tissue healing.
It is obvious that the materials of the invention can also include various additives for facilitating processing of the material (e.g. stabilizers, anti-oxidants or softeners) or for altering its properties (e.g. softeners or powder-like ceramic materials or biostable fibres, such as polyaramid or carbon fibres) or for facilitating its handling (e.g. colorants).
The accompanying dependent claims present some advantageous embodiments of the material according to the invention.
The invention also relates to a method for manufacturing under tissue conditions absorbable material. The method is mainly characterized by features presented in the characterizing part of the accompanying independent claim relating to the method.
Advantageous embodiments of the method are presented in the accompanying independent claims.
When manufacturing materials in accordance with the invention, a molecular orientation is carried out by modifying biomaterial in solid state mechanically in a temperature where large scale molecular movements are possible, but where thermal movement is not strong enough for the achieved orientation to relax as a result from the molecular thermal movements.
The simplest way of performing the mechanical modification is to draw a melt-processed (such as injection molded, extrusion molded or compression molded), non-oriented billet or preform (such as a rod, plate or film) to a typical drawing ratio of 2 to 6 in the direction of the longitudinal axis of the billet. The drawing can also be carried out as a so called die drawing, wherein the billet is drawn through heated die to a suitable drawing ratio. As a result of the drawing, the molecule chains and/or parts thereof are directed increasingly to the draw direction, wherein the strength and toughness of the material are growing in the draw direction. After the drawing, the drawn billet is cooled under stress to room temperature, and various implants can be further processed thereof, such as rods, screws, plates, pins, hooks, stents, spirals etc. Suitable processing methods are e.g. turning, milling, shearing and other mechanical processing methods, thermal processing (compression molding under heat and pressure) or combinations of mechanical processing and thermal processing.
During drawing, the billet or die can also be turned around the longitudinal axis of the billet, wherein a spiral orientation is obtained thereto, which is particularly advantageous e.g. in screws.
For plate-formed and foillike preforms, also two-axial drawing can be carried out, wherein orientation is obtained for the billet also in a direction perpendicular to its longitudinal axis.
Materials of the invention can be manufactured of said raw materials also by using so-called solvent methods, wherein at least a part of the polymer is solved into a suitable solvent or softened by the solvent and the material or the material combination is compressed to a piece by using pressure and possibly a slight heat, wherein the solved or softened polymer glues the material to a macroscopic piece, from which the solvent is eliminated by evaporating. Techniques of this type are suitable particularly when manufacturing thermosensitive enzymes, peptides and proteins, such as implants containing BMP-molecules.